4-phenyl-1-alkyl isonipecotic acid lactones



Patented Mar.14,1950 7 I I 2,500,714

UNITED STATES PATENT OFFICE 4-PHENYL-1-ALKYL ISONIPECOTIC ACID LACTONESMarvin A. Spielman, Waukegan, 111., assignor to Abbott Laboratories,North Chicago, Ill., a corporation of Illinois No Drawing. ApplicationOctober 30, 1944, Serial No. 561,171

9 Claims. (01. 260-294) 1 2 The present invention relates to newtherawhere R1 is an aryl group containing at least peutic products andparticularly to products one alkoxy group in a position ortho to thecharacterized by analgesic properties. piperidine ring; and R2, R3; R4,R5, and Rs are The products of my invention may be repre- Hor alkylgroups, sented by the following general formula: 5 Treatment of thenitrile with a concentrated 0 aqueous solution of a hydrogen halide byrefluxing several hours yields the desired isonipecotic 7 acid lacetone.Conversion of the nitrile to the 2 lactone may also be efiected bytreatment with in which R1 is a benzene rin with two adjacent l0 alkalifollowed by ea ment wi h acid. The carbon atoms common to the furanonering; and lactones have the following formula: R2 is a piperidine ringwith a single carbon atom common to the furanone ring; R1 and R2 havingH no unduly toxic substituents. H

The basic structure of the compounds of the 0:0 present invention isknown in the art as a deriv- H ative of isonipecotic acid. Thesecompounds are all substituted isonipecotic acid lactones formed H by theintroduction of an o-hydroxyaryl group 11-0 o n into isonipecotic acid.They are basic in reaction I and form crystalline salts with the commonacids. For example the compound called 4-(6'- 7 QZhydroXy-3'-methylphenyl) 1 methyl-isonipe- 1 R3 R5 cotic acid lactonehydrochloride has the formula: N

H I Ra i in which X denotes a non-toxic substituent for CH3 72 one ormore of the hydrogens of the ring, such 0 1110 son, as alkyl or halogen.H A 26112 The isonipecotic acid lactones have been found 1 to possessanalgesic properties. They are usually HO] administered as the saltsmade by reacting the CH3 lactones with an acid such as hydrochloricacid.

In the preparation of compounds having the The salt may be given orallyin tablet or capsule same ring skeleton as isonipecotic acid, thestarting materials are a di-(fi-halogenalkyl) -amine parentem11yand anaryl acetonitrile, containing one alkoxy follofvmg eamples are glven asIllustragroup in the ortho position and any other detlons of themventlon:

sired substituents elsewhere on the benzene ring.

These two compounds in the presence of soda- EXAMPLE I mide react withelimination of two molecules (a) 2-metho,1jy 5-methylphenyla,cetonitrileof hydrogen halide to form the corresponding4-arylpiperidine-4-carboxy1ic acid nitriles hav- 00113 ing the generalformula:

R1 0N H CHzCN.

H H RzHC CHR4 CH3 RaH HR];

One hundred seventy-five grams of commercial R6 formalin was saturatedwith hydrogen chloform, or made into a solution and given orally or 400g. sodium cyanide, 400 cc. water, and two liters of acetone. Most of theacetone. was boiled 011'. The mixture was diluted, extracted with etherand distilled. The yield was 288 g., boiling point 109-110 C. under apressure of about (b) 4- (6-methoary-3'-methylphenyl) -1-methylz'sonipecotonitrile allowed to evaporate as 200 cc. of toluene, wa

added.

One hundred grams of bis-(,c-chloroethyl) methylamine hydrochloride wasplaced in a 500 cc. flask, covered with 200 cc. of ether and then 100cc. of 50% sodium hydroxide was added. The

contents of the flask were agitated several minutes and then allowed to.separate'into two layers. Th upper layer which was an ether solution ofhis (p-chloroethyl) methylamine was separated; 100 cc. of benzene wasadded-and'the-solvent was then rapidly removed byevaporation in vacuowith caution to keep the temperature below 30 C. The free base-was leftas an oil.

In a 3-neck flask fitted with a stirrer-and reflux condenser was placedthe freshly liberated bas from 100 g. bis (p-chloroethyl) -methy1aminehydrochloride (prepared as described in the previous paragraph), 80 g.of 2-methoxy 5-methylphenylacetonitrile and 500 cc. toluene. Thesodamide (prepared as described in the first paragraph) was added inportions with stirring as the reaction proceeded at 40-55 C. At the end,the mixture was boiled for one hour.

The cooled toluene solution was washed once with water, then extractedwith hydrochloric acid. Theaqueous layer was made alkaline, the basicprecipitate was extracted with ether and finally distilled in vacuo. Theproduct boiled at 150-155 C. under a pressure of 3 mm. The yield was40%-60% of a very viscous colorless liquid. Scratching inducedcrystallization. The solid melted at'63'-64 C. after recrystallizationfrom petroleum ether.

(c) 4'6-hydroa:y-3'-methylphenyl)-1-methyl isonipecotz'c acid lactone 7Fifty-eight gramsof 4-(6-methoxy-3'-methylphenyl)-1-methylisonipectonitrile was boiled over-night under a refluxcondenser with 200 cc. constant boiling hydrobromic acid. Most of theacid was removed in vacuo; the residue was covered with ether and shakenwith an excess of aqueous sodium carbonate. The ether solution of thefree base was roughly dried over sodium sulfateand an excess of etherealhydrogen chloride was added. Thehydrochloridesalt came down at once andsoon crystallized; It was recrystallized from absolute alcohol meltingpoint 269-271 C.

The free base melted at 83-84 after crystallization from ether.

The hydrobromide, which was prepared by treating the base with hydrogenbromide in a manner similar to that'used inpreparingth'e hydrochloride,melting at 265-268 C. r

The analgesic dose of the hydrochloride for adult-humans is 50 mg. to'200' mg. It may be given orally in the form of tablets, capsules "orsolution, or parenterally in aqueous solution;

If the 2-methoxy 5 methylphenylacetonitrile used :in Example I isreplaced by o-metho'x'yphenylacetonitrile' the-product obtained will be(Gf-h'ydrQXyphenyI) -l-m'ethylisonipecotic acid lactone which forms ahydrochloride melting at 258-259 C., and which has the'followin'g'st'ructural formula:

This compound has been tested-on experimental animals and found to'exertananalgesic efi'ect in a dosage of 700' mg. per kilogram, while theminimum lethal dose for 50% mortality is 1500 mg. per kg.

- EXAMPLE III ride melting at 250-251 C., and which has the followingstructural formula:

The dosage for the hydrochloride of this compound is the same as forExample II.

EXAMPLE IV If the 2-methoxy-5-methylphenylacetonitrile used in Example Iis replaced by 2-methoxy-5- ethylphenylacetonitrile the product obtainedwill be 4- (3' -ethyl-6-hydroxyphenyl) -l-methylisonipecotic acidlactone which forms a hydrochloride melting at 246-248 C., and which hasthe following structural formula:

For mice, the analgesic dose of the hydrochloride is 50 mg. per kilo ofbody weight. The M. L. D. dose is 100 mg. per kilo of body weight. Theexpression M. L. D. 50 means dose which kills approximately 50 per centof the animals tested.

EXAMPLEV If the 2-methoxy-5-methylphenylacetonitrile used in Example Iis replaced by 2-methoxy-5-npropyl acetonitrile the product obtainedwill be 4 (6 hydroxy 3'-n-propylphenyl) -1-methylisonipecotic acidlactone which forms a hydrochloride melting at 258-260 C., and which hasthe following structural formula:

For mice, the analgesic dose of the hydrochloride is 75 mg. per kilo ofbody weight. The M. L. D. dose is 150 mg. per kilo of body weight.

EXAMPLE VI If the 2-methoxy-5-methylphenylacetonitrile used in Example Iis replaced by 2-methoxy-5- chlorophenylacetonitrile the productobtained will be 4-(3'-chloro-6'-hydroxyphenyl)-1-methyl isonipecoticacid lactone which forms a hydror 6 chloride melting at 285-288 0., andwhich has the following structural formula:

For mice, the analgesic dose of the hydrochloride is 200 mg. per kiloof' body weight. The M. L. D. dose is 400 mg. per kilo of body weight.

EXAMPLE VII If the bis-(p-chloroethyl) methylamine is replaced bybis-(B-chloroethyl)-ethylamine, in Example I, the product obtainedwillbe 4-(6'- hydroxy-3'-methylphenyl) 1 ethylisonipecotic acid lactonewhich forms a hydrochloride melting at 262-263 C. and which has thefollowing structural formula:

The hydrochloride of this compound has been administered to adulthumans. A good analgesic effect with no deleterious effects is securedwith a dose of mg.

( a) 1 -benzoyl-4- (6'-meth0a:y-3' -methylphenyl) isonipecotonitrile H ono QHr OOH| I H 0 HI tionf froml zalcohdi3 the melting polntfirose 'to(b) 4- (6'-hydro:cy-3 -methylphenyl) -isonipecotic acid lactone Thirtygrams of the above nitrile was boiled -cunder a: reflux: oondensersiforll2pihours "with 150 oscc'. ofsco'nstant: hoiling; hydrobromic acid.;i-Itrwas "evaporated ?-to.- ari pastes in -.,.vacuo;:ecovereda with 200cc. of ether and made alkaline by violent agitation withian :excess of,sodium carbonate, solution. The basic portion in the ether was..-..conver ted..torthe hydrochloride vbyeaddition of ethereal;hydrogenzzchloride i-after crystallization 'fromnetha-noldioxan,ihmelted zit-164 C.

.This com-pound produces: Tanalgesia. in mice .---with apdosage of =75mgeperrkg-a ofobody" weight and:the.minimum.slethaldose ion-:50'mortality is 150 mg. per kg.

(c) The above product was conveniently converted to 4- (6-hydroxy 3methylphenyl-l methylisonipecotic acid lactone (the product of ExampleI) by methylation. of the nitrogen atom by boiling 25 g: overnight with12 cc. formalin and cc. formic-.acid. The .m-iXture was concentrated toa syrup,..tr'eated with sodium car; bonate under (ether; andsconvertedto the hydrochloride-*by. ethereal or alcoholic hydrogen chloride.

EXAMPLE IX Sulfate of '4-(6-hydr0xy-3'-methylphenyl) -1-methylisonipecotic acid lactone -By =treating.ithei .free -basewithrethereal: zsulphuric acid I '(in airman-nex :similare tozzthat :de-

scribed in Example I (cwforrpreparingitheihydrochloride) the crystallinesulfate is obtained, being the addition salt of the lactone and sulfuricacid. It melts at31'99fZ 20Mc,

Without further elaboration, the foregoing will so fully explain my 4invention that 1 others may readily adapt the='same for-'-use undervarious" conditions of service.

It will, for instance, :be obvious that suitable additioncompoundsothenthan those specifically set forth in detail herein may beproduced without invention:;For the purposes of this specifica tion, anadditiomcomp'ound of piperidine is defined as a compound formed by theunion of piperidine with another group of atoms, without apparentz'alteration or rupture of the pipe: ridine ring or anynther part of thelarger mole cule in which said ring is included, said other group ofatomsbeing capable of existing as an independent and complete moleculeby itself.

.. acid a'dditionproducts thereof in whiclithe'lactone compoundscontainingone' benzene ring and .onepipefidifie ring .are'representedjby theifollowing (general formula:

-incwhich' st is aineinberr anther-group: consistin vaphenyl)-1.-methylisonipecotic acid lactonewhich has the formula and acid saltsthereof.

5. The compound 4-=.(6'-hydroxy-3-methylphenyl)-l-methylisonipecotic.-acid lactone hydrochloride represented by the formula 6. A memberselected from the groupconsisting of the compound4-.(3.f-chloro-6-hydroxyphenyl) -1-methylisonipecoti'c acid lactonewhich is represented by the formula and acid salts-thereof.

7. The compound 4-(3-chloro-6'-hydroxyphenyl) -1-inethylisonipecoticacid lactone hydrochloride which is represented by the formula 8: Amember-selected fromth'e groupconsisting ofthe compound 4- 6"-'hydroxy3"-methylg phenyl)-l-ethy1isonipecotic acid lactone is represented bythe formula 9. The compound 4-(6'-hydroXy-3-methy1- phenyl)-1-ethy1isonipecotic acid lactone hydrowhich chloride which isrepresented. by the formula (132115 .HOl

MARVIN A. SPIELMAN.

REFERENCES CITED The following references are of record in the file ofthis patent:

5 UNITED STATES PATENTS Number Name Date 2,044,015 Perkins et a1. June16, 1936 2,167,351 Eisleb July 25, 1939 10 OTHER REFERENCES Bergel et211., J. Chem. 800., June 1944, pages 261-269.

1. ISONIPECOTIC ACID LACTONE COMPOUNDS AND ACID ADDITION PRODUCTSTHEREOF IN WHICH THE LACTONE COMPOUNDS CONTAINING ONE BENZENE RING ANDONE PIPERIDINE RING ARE REPRESENTED BY THE FOLLOWING GENERAL FORMULA: